The present invention relates to combinations of antiviral agents. More particularly, it relates to combinations of HIV-1 protease inhibitors which exhibit lack of cross-resistance and are thus desirable in the clinical treatment of HIV infection.
Human Immunodeficiency Virus (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) in man. There are currently only three drugs approved for the treatment of HIV infection in the United States, AZT (zidovudine; Retrovir.RTM.), DDI (didanosine, Videx.RTM.) and DDC (zalcitabine, Hivid.RTM.). All three are members of the nucleoside analog class which inhibit the activity of the HIV-1 reverse transcriptase enzyme. These nucleoside analogs have shown efficacy in the clinical setting. However, none of them appear to halt disease progression, and treatment, particularly with AZT, results in viral variants that have significantly reduced drug sensitivity.
The HIV-1 reverse transcriptase has proven to be a very accommodating enzyme that is capable of harboring several amino acid substitutions that render it resistant to individual nucleoside analogs or a combination of nucleoside and/or non-nucleoside analogs.
HIV-1 also encodes an aspartyl protease enzyme that plays an essential role in reproduction of the virus late in infection and represents an attractive target for drug intervention. Recently, several inhibitors of this protease have been reported in the literature. Since these protease inhibitors, unlike reverse transcriptase inhibitors, have the ability to inhibit the production of infectious virus particles in chronically-infected cells, they are promising candidates for anti-HIV therapy.
Our parent U.S. application Ser. No. 07/79,978 filed Jun. 25, 1993 describes novel aminediol HIV-1 protease inhibitors of the following formula I ##STR1## where A.sup.a, A.sup.b and A.sup.c are independently:
(1) hydrogen; PA1 (2) alkyl, especially lower alkyl; ##STR2## D.sup.a and D.sup.b are independently selected from groups of the formula: ##STR3## where D.sup.a and D.sup.b are bonded to the groups A.sup.a and A.sup.b, respectively, through the moiety --E--N(R.sup.8)--, where E is a single bond or a peptide chain containing 1 to 4 amino acids, the N-terminus of which is bonded to A.sup.a when E is part of D.sup.a or to A.sup.b when E is part of D.sup.b ; PA1 (1) hydrogen; PA1 (2) alkyl, especially lower alkyl; PA1 (3) alkenyl, especially lower alkenyl; PA1 (4) aryl; PA1 (5) heterocyclo; or PA1 (6) carbocyclo, such as cycloalkyl; PA1 (a) hydrogen; PA1 alkyl, especially lower alkyl; PA1 (c) aryl; PA1 (d) heterocyclo; PA1 (e) carbocyclo, such as cycloalkyl; PA1 (f) when R.sup.3 and R.sup.4 are bonded to a common nitrogen atom, R.sup.3 and R.sup.4 may be joined, together with that nitrogen atom, to form a heterocyclic ring system, such as a 5 to 7 membered heterocyclic ring; or PA1 (g) when E is a single bond and R.sup.3 is part of A.sup.a or A.sup.b, R.sup.3 may, together with R.sup.8, form an alkylene group, for example, having one to five carbons, such as wherein R.sup.3 and R.sup.8, together with the atoms to which they are bonded, form the cyclic moiety: ##STR4## R.sup.5, R.sup.6 and R.sup.7 are independently: (a) hydrogen; PA1 (b) alkyl, especially lower alkyl; PA1 (c) aryl; PA1 (d) carbocyclo, such as cycloalkyl; PA1 (e) fluorenyl; PA1 (f) heterocyclo; PA1 (g) R.sup.5, R.sup.6 and R.sup.7 may, independently, be joined, together with the carbon atom to which they are bonded, to form a mono-, bi- or tricyclic carbocyclic ring system, especially wherein each ring contains 3 to 7 carbon atoms, or a mono-, bi- or tricyclic heterocyclic ring system; PA1 (h) alkynyl; PA1 (i) alkenyl; or PA1 (g) when E is a single bond and R.sup.5, R.sup.6 and R.sup.7 are part of A.sup.a or A.sup.b, one of R.sup.5, R.sup.6, or R.sup.7 may, together with R.sup.8, form an alkylene group, for example, having one to three carbons, such as wherein R.sup.5 and R.sup.6 are methyl and R.sup.7 and R.sup.8, together with the atoms to which they are bonded, form the cyclic moiety: ##STR5## R.sup.8 is: (a) hydrogen; PA1 (b) alkyl, especially unsubstituted lower alkyl or aryl-lower alkyl; PA1 (c) R.sup.8 and R.sup.9 may be joined, together with the atoms to which they are bonded, to form a heterocyclic ring system, for example, a 5 to 7 membered monocyclic heterocyclic ring; PA1 (d) R.sup.8 may be joined together with R.sup.5, R.sup.6 or R.sup.7 as described above; PA1 (e) R.sup.8 may be joined together with R.sup.3 as described above; or PA1 (f) R.sup.8 and R.sup.11 may be joined, together with the atoms to which they are bonded, to form a heterocyclic ring system, such as where R.sup.8 and R.sup.11 together are an alkylene group; PA1 (a) hydrogen; PA1 (b) alkyl, especially lower alkyl; PA1 (c) alkenyl, especially lower alkenyl; PA1 (d) alkynyl; PA1 (e) aryl PA1 (f) heterocyclo; PA1 (g) carbocyclo, such as cycloalkyl; PA1 (h) R.sup.9 may be joined together with R.sup.8 as described above; or PA1 (i) R.sup.9 and R.sup.9' may be joined, together with the carbon atom to which they are bonded, to form a carbocyclic group, such as 5- or 6-membered carbocyclic ring; PA1 (a) hydrogen; PA1 alkyl, such as unsubstituted lower alkyl or hydroxy-lower alkyl, cycloalkyl-lower alkyl, aryl-lower alkyl or heterocyclo-lower alkyl; PA1 (c) alkenyl, especially lower alkenyl; PA1 (d) alkynyl; PA1 (e) carbocyclo, such as cycloalkyl; PA1 (f) aryl; or PA1 (g) R.sup.l0 and R.sup.11 taken together may form a bond to give a keto (C.dbd.O) group; PA1 (a) hydrogen; PA1 (b) a hydroxyl protecting group, such as alkyl; PA1 (c) R.sup.11 may be joined together with R.sup.8 as described above; or PA1 (d) R.sup.11 may, together with R.sup.10, form a bond to give a keto group as described above;
R.sup.1 and R.sup.2 are independently:
R.sup.3 and R.sup.4 are independently:
R.sup.9 and R.sup.9' are independently:
R.sup.10 is:
R.sup.11 is:
Z is oxygen or sulfur; and p and q are, independently, integers from 0 to 4; and salts, preferably pharmaceutically acceptable salts, thereof. Among the compounds disclosed is [1S-[1R*,2S*(2S*,3R*)]]-[3-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hyd roxy-4-(4-[2-(4-morpholinyl)-2-oxo-ethoxy]phenyl]butyl]amino]-2-hydroxy-1-( phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester, the structure of which is as follows: ##STR6## This compound will also be referred to below as BMS-186318.
Preferred embodiments of BMS-186318 include the pharmaceutically acceptable salts formed with inorganic and/or organic acids, e.g. succinic acid, acetic acid, hydrochloric acid, fumaric acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, maleic acid and tartaric acid. The succinate salt of BMS-186318 is a particularly preferred embodiment.
EP 432695 A2 discloses the Hoffmann-LaRoche HIV-1 protease inhibitor of the formula ##STR7## which is known as saquinavir or Ro 31-8959. This compound has the chemical name N-tert.butyl-decahydro-2(2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbony l)-L-asparaginyl)amino)butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide.
PCT Published Application WO 92/08688 discloses the Monsanto-Searle HIV-1 protease inhibitor designated SC-52151 having the formula ##STR8## and the chemical name [1S-[1R*(R*), 2S*]]-N.sup.1 [3-[[[(1,1-dimethylethyl)amino]-carbonyl](2-methylpropyl)amino]-2-hydroxy- 1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide.
EP 402646 A1 discloses the Abbott HIV-1 protease inhibitor designated A-77003 having the formula ##STR9## and the chemical name (2S,3R,4S,5S)-2,5-di-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)- valinyl-amino)-3,4-dihydroxy-1,6-diphenylhexane.
The Abbott HIV-1 protease inhibitor designated ABT-538 having the formula ##STR10## and the chemical name, [1S-(1R,2R,4R)]-N-[2-hydroxy-5-phenyl-1-(phenylmethyl)-1-[[(5-thiazolylmet hoxy)carbonyl]amino]pentyl]-N.sup.2 -[[N-methyl[[2-(1-methylethyl)-4-thiazolyl]methyl]amino]carbonyl]L-valinam ide, is generically disclosed in EP 486948 A2 and specifically disclosed in an abstract for the 207th American Chemical Society meeting (Mar. 13-17, 1994) held in San Diego, Calif.
EP 486948 A2 discloses the Abbott HIV-1 protease inhibitor designated A-80987 having the formula ##STR11## and the chemical name (2S,3S,5S)-2-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)amino)-5-(N-((3- pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.
EP 541168 A1 discloses the Merck HIV-1 protease inhibitor designated L-735,524 having the formula ##STR12## and the chemical name N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-py ridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide.
The Agouron HIV-1 protease inhibitor designated AG-1343 having the formula ##STR13## and the chemical name [3S-[2(2S*,3S*)3a,4ab,8ab]]-N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3- [(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarbo xamide was disclosed, for example, by V. Kalish of Agouron at the 1st Winter Bioorganic/Medicinal Chemistry Symposium held at Steamboat Springs, Colorado on January 29-Feb. 2, 1995 (see also, Rev. Med. Virol. 5: 23-33, 1995).
AG-1343 may be prepared by reacting the amine of the formula ##STR14## (prepared as described in Jungheim, et al., European Published Application 604,185A1) with the acid ##STR15## (prepared as described in U.S. Pat. No. 5,110,979; Houbion, et al. in Org. Prep. Proced. Int., 1979, 11, 27; and Cresp, et al., in J. Chem. Soc. Perkins Trans. I, 1974, 2435) under standard peptide coupling conditions, e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC)/hydroxybenzotriazole (HOBT).
The above-described Hoffmann-LaRoche, Monsanto-Searle, Agouron, Abbott and Merck HIV-1 protease inhibitors have all been reported to be under clinical development for HIV infection.
Various suggestions have been made in the literature to combine antiviral drugs, including HIV protease inhibitors, with other antiviral agents (see, for example, Antimicrob. Agents Chemother. 36(3), 509-520, 1992; J. Acquired Immune Deficiency Syndromes, 3 (Suppl. 2), S99-S103, 1990; and J. Acquired Immune Deficiency Syndromes, 6, 162-170, 1993). PCT Application WO 94/02149 discloses the so-called convergent combination approach to antiviral therapy whereby an antivirally effective amount of three or more different agents are employed, each of which is capable of inhibiting the activity of the same gene product or gene of a virus.
Suppressing chronic HIV infection requires long-term therapy. We have found that although the HIV virus appears to have more difficulty becoming resistant to protease inhibitors than to non-nucleoside reverse transcriptase inhibitors, resistance eventually does develop to HIV protease inhibitors. In-vitro drug sensitivity assays on the HIV-1 protease inhibitors currently in clinical trials have demonstrated unique resistance profiles, suggesting that combination of two or more protease inhibitors may be an effective approach to inhibiting HIV replication.
It is an object of the present invention to provide certain combinations of HIV-1 protease inhibitors which, when used either concurrently or sequentially, overcome the drug resistance seen with use of individual HIV-1 protease inhibitors or many combinations of HIV-1 protease inhibitors.